The PI3K-AKT pathway is an important signaling pathway which plays a central role in growth, proliferation, differentiation, invasion, migration, apoptosis, glucose metabolism, and the like of cells. It has been known that in plural malignant tumors, the PI3K-AKT pathway is constantly activated by activation of receptors upstream of the PI3K-AKT pathway and mutation, deficiency, and amplification of the molecules constituting the PI3K-AKT pathway (Nature Reviews Drug Discovery Vol. 8, No. 8, pp. 627-644, 2009).
It has been reported that the PI3K-AKT pathway contributes to not only malignant tumors but also other diseases such as, for example, cell proliferative diseases, allergy and autoimmune diseases, neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, endocrine abnormalities, metabolic abnormalities, and infectious diseases (Biochimica et Biophysica Acta, Vol. 1784, No. 1, pp. 159-185, 2008).
Therefore, it is believed that control of the PI3K-AKT pathway would be beneficial in the treatment of various diseases.
The Ras-Raf-MEK-ERK pathway is a pathway which is located downstream of various receptors and plays an important role in cell physiological functions such as, for example, cell proliferation, apoptosis, and cell differentiation (ChemMedChem, Vol. 6, No. 1, pp. 38-48, 2011).
Examples of diseases in which the Ras-Raf-MEK-ERK pathway is involved include malignant tumors, allergy and autoimmune diseases, cardiovascular diseases, and neurodegenerative diseases.
Therefore, control of the Ras-Raf-MEK-ERK pathway is expected to be beneficial in the treatment of various diseases.
Here, the PI3K-AKT pathway and the Ras-Raf-MEK-ERK pathway function in cell proliferation in a complementary manner, and it has been reported that simultaneous control of both of the pathways is beneficial in the treatment of malignant tumors (Cancer Biology & Therapy, Vol. 7, No. 2, pp. 307-315, 2008, and Nature medicine, Vol. 14, No. 12, pp. 1351-1356, 2008).
Since the PI3K-AKT pathway and the Ras-Raf-MEK-ERK pathway are very important for the treatment of diseases, PI3K-AKT pathway inhibitors or Ras-Raf-MEK-ERK pathway inhibitors have been hitherto developed. However, compounds which have led to commercial launch are extremely rare (International publication WO 2011/064250). In addition, there have only been a few reports of compounds which inhibit directly and simultaneously both of the signaling pathways (Japanese National-Phase Publication (JP-A) No. 2009-515854).
On the other hand, a 1,5-naphthyridine derivative having a urea structure in a molecule thereof, which inhibits Aurora B, the Ras-Raf-MEK-ERK pathway, and Erk2 (International publication WO 2011/064250) has been known. However, a 1,5-naphthyridine derivative which has a urea structure in a molecule thereof and inhibits a PI3K-AKT pathway has not been known.
In International publication WO 2011/064250, it is described that a 1,5-naphthyridine derivative having a urea structure in a molecule thereof can be prepared from 7-bromo-2-chloro-1,5-naphthyridine.
As a method for preparing 7-bromo-2-chloro-1,5-naphthyridine, a method in which 3-bromo-1,5-naphthyridine is oxidized with m-chlorobenzoic acid and then halogenated with phosphorous oxychloride (International publication WO 2011/064250) has been described.
However, this preparation method has drawbacks such as (1) a low yield, (2) the need for column chromatography, and (3) the expensiveness of and difficulty of obtaining 3-bromo-1,5-naphthyridine which is a raw material.